Enolates are among the most common carbon nucleophiles, but reactions of these nucleophiles with aryl or vinyl electrophiles do not occur in the absence of catalyst. During the past grant period, we discovered and developed palladium complexes containing sterically hindered alkylphosphines that catalyze the coupling of several types of enolates with aryl halides in high yields with high turnover numbers. We propose to use as a launching pad for future studies recent preliminary data on new classes of enolate couplings and new classes of isolated palladium complexes. These studies will combine the development of synthetic methods with quantitative mechanistic experiments to create a conceptual framework that allows one to choose appropriate catalysts and predict reaction scope. Although arylations of ketones, esters, malonates and cyanoesters now occur efficiently with several types of aryl halides, the reactions of other common carbonyl compounds and nitriles are not yet efficient enough for widespread use in syntheses. Proposed studies will address these current limitations. We will develop methods to form quaternary amino acids directly from natural amino acids, use mechanistic data to improve amide and nitrile alpha-arylations, synthesize optically active, electron-rich phosphines for enantioselective couplings, and develop conditions for alpha-arylation of enolates in neutral media. Neutral media will tolerate a wider range of functional groups, increase selectivity for monoarylation, and create the potential to control enantioselectivity at enolizable stereocenters. Mechanistic studies will delineate the chemistry of reaction intermediates and the kinetic behavior of the overall catalytic cycle. We will study the formation and reactions of the first three-coordinate arylpalladium halide complexes, which are true intermediates in the coupling of enolates as well as other nucleophiles. We will study the reaction chemistry of arylpalladium complexes of functionalized alkyl groups to uncover, for the first time, the effect of alkyl group electronics on reductive elimination and will determine how the recently developed, highly active catalysts react with aryl chlorides and tosylates. Recent data suggests that the high activity of the catalyst is created, in part, by coordination of stoichiometric base, halide byproduct, or nucleophile to palladium(0) prior to reaction with aryl chloride or tosylate. Experiments on catalytic reactions and single turnovers are presented that will test this proposal in efficient catalytic systems.